Behavioral changes following PCB 153 exposure in the spontaneously hypertensive rat - an animal model of Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a behavioral disorder affecting 3-5% of children. Although ADHD is highly heritable, environmental factors like exposure during early development to various toxic substances like polychlorinated biphenyls (PCBs) may contribute to the prevalence. PCBs are a group of chemical industrial compounds with adverse effects on neurobiological and cognitive functioning, and may produce behavioral impairments that share significant similarities with ADHD. The present study examined the relation between exposure to PCB 153 and changes in ADHD-like behavior in an animal model of ADHD, the spontaneously hypertensive rats (SHR/NCrl), and in Wistar Kyoto (WKY/NHsd) controls. METHODS: SHR/NCrl and WKY/NHsd, males and females, were orally given PCB 153 dissolved in corn oil at around postnatal day (PND) 8, 14, and 20 at a dosage of 1, 3 or 6 mg/kg bodyweight at each exposure. The control groups were orally administered corn oil only. The animals were behaviorally tested for exposure effects from PND 37 to 64 using an operant procedure. RESULTS: Exposure to PCB 153 was associated with pronounced and long-lasting behavioral changes in SHR/NCrl. Exposure effects in the SHR/NCrl depended on dose, where 1 mg/kg tended to reduce ADHD-like behaviors and produce opposite behavioral effects compared to 3 mg/kg and 6 mg/kg, especially in the females. In the WKY/NHsd controls and for the three doses tested, PCB 153 exposure produced a few specific behavioral changes only in males. The data suggest that PCB 153 exposure interacts with strain and sex, and also indicate a non-linear dose-response relation for the behaviors observed. CONCLUSIONS: Exposure to PCB 153 seems to interact with several variables including strain, sex, dose, and time of testing. To the extent that the present findings can be generalized to humans, exposure effects of PCB 153 on ADHD behavior depends on amount of exposure, where high doses may aggravate ADHD symptoms in genetically vulnerable individuals. In normal controls, exposure may not constitute an environmental risk factor for developing the full range of ADHD symptoms, but can produce specific behavioral changes.

Marine Ο-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behaviour and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD.

BACKGROUND: Previous reports suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFA) supplements may reduce ADHD-like behaviour. Our aim was to investigate potential effects of n-3 PUFA supplementation in an animal model of ADHD. METHODS: We used spontaneously hypertensive rats (SHR). SHR dams were given n-3 PUFA (EPA and DHA)-enriched feed (n-6/n-3 of 1:2.7) during pregnancy, with their offspring continuing on this diet until sacrificed. The SHR controls and Wistar Kyoto (WKY) control rats were given control-feed (n-6/n-3 of 7:1). During postnatal days (PND) 25-50, offspring were tested for reinforcement-dependent attention, impulsivity and hyperactivity as well as spontaneous locomotion. The animals were then sacrificed at PND 55-60 and their neostriata were analysed for monoamine and amino acid neurotransmitters with high performance liquid chromatography. RESULTS: n-3 PUFA supplementation significantly enhanced reinforcement-controlled attention and reduced lever-directed hyperactivity and impulsiveness in SHR males whereas the opposite or no effects were observed in females. Analysis of neostriata from the same animals showed significantly enhanced dopamine and serotonin turnover ratios in the male SHRs, whereas female SHRs showed no change, except for an intermediate increase in serotonin catabolism. In contrast, both male and female SHRs showed n-3 PUFA-induced reduction in non-reinforced spontaneous locomotion, and sex-independent changes in glycine levels and glutamate turnover. CONCLUSIONS: Feeding n-3 PUFAs to the ADHD model rats induced sex-specific changes in reinforcement-motivated behaviour and a sex-independent change in non-reinforcement-associated behaviour, which correlated with changes in presynaptic striatal monoamine and amino acid signalling, respectively. Thus, dietary n-3 PUFAs may partly ameliorate ADHD-like behaviour by reinforcement-induced mechanisms in males and partly via reinforcement-insensitive mechanisms in both sexes.

Postnatal exposure to PCB 153 and PCB 180, but not to PCB 52, produces changes in activity level and stimulus control in outbred male Wistar Kyoto rats.

BACKGROUND: Polychlorinated biphenyls (PCBs) are a class of organic compounds that bioaccumulate due to their chemical stability and lipophilic properties. Humans are prenatally exposed via trans-placental transfer, through breast milk as infants, and through fish, seafood and fatty foods as adolescents and adults. Exposure has several reported effects ranging from developmental abnormalities to cognitive and motor deficiencies. In the present study, three experimental groups of rats were orally exposed to PCBs typically found in human breast milk and then behaviorally tested for changes in measures of stimulus control (percentage lever-presses on the reinforcer-producing lever), activity level (responses with IRTs > 0.67 s), and responses with short IRTs (< 0.67 s). METHODS: Male offspring from Wistar Kyoto (WKY/NTac) dams purchased pregnant from Taconic Farms (Germantown, NY) were orally given PCB at around postnatal day 8, 14, and 20 at a dose of 10 mg/kg body weight at each exposure. Three experimental groups were exposed either to PCB 52, PCB 153, or PCB 180. A fourth group fed corn oil only served as controls. From postnatal day 25, for 33 days, the animals were tested for behavioral changes using an operant procedure. RESULTS: PCB exposure did not produce behavioral changes during training when responding was frequently reinforced using a variable interval 3 s schedule. When correct responses were reinforced on a variable interval 180 s schedule, animals exposed to PCB 153 or PCB 180 were less active than controls and animals exposed to PCB 52. Stimulus control was better in animals exposed to PCB 180 than in controls and in the PCB 52 group. Also, the PCB 153 and PCB 180 groups had fewer responses with short IRTs than the PCB 52 group. No effects of exposure to PCB 52 were found when compared to controls. CONCLUSIONS: Exposure to PCBs 153 and 180 produced hypoactivity that continued at least five weeks after the last exposure. No effects of exposure to PCB 52 were observed.

The spontaneously hypertensive rat model of ADHD--the importance of selecting the appropriate reference strain.

Although several molecular and genetic manipulations may produce hyperactive animals, hyperactivity alone is insufficient for the animal to qualify as a model of ADHD. Based on a wider range of criteria - behavioral, genetic and neurobiological - the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany (SHR/NCrl) at present constitutes the best validated animal model of ADHD combined subtype (ADHD-C), and the Wistar Kyoto substrain obtained from Harlan, UK (WKY/NHsd) is its most appropriate control. Although other rat strains may behave like WKY/NHsd rats, genetic results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable controls for the SHR/NCrl. The use of WKY/NCrl, outbred Wistar, Sprague Dawley or other rat strains as controls for SHRs may produce spurious neurobiological differences. Consequently, data may be misinterpreted if insufficient care is taken in the selection of the control group. It appears likely that the use of different control strains may underlie some of the discrepancies in results and interpretations in studies involving the SHR and WKY. Finally, we argue that WKY rats obtained from Charles River, Germany (WKY/NCrl) provide a promising model for the predominantly inattentive subtype of ADHD (ADHD-PI); in this case also the WKY/NHsd substrain should be used as control.